Project Summary/Abstract The basal ganglia are a series of inter-connected brain nuclei that control voluntary movement through the coordination of two parallel neural circuits, the 'direct pathway' that facilitates movement and the 'indirect pathway' that suppresses movement. Imbalances between these two pathways are hypothesized to underlie movement disorders such as Parkinson's disease, Huntington's disease, Tourette syndrome, and dystonia. My long-term goal is to identify cellular mechanisms of direct and indirect pathway regulation to better understand the neuronal basis of motor control in both health and disease. Neuronal circuits in the striatum, the input nucleus of the basal ganglia, are particularly important in determining direct and indirect pathway activity, but their organizing principles remain poorly understood. The objective of this proposal is to identify the role of fast-spiking (FS) interneurons in regulating striatal output. In Aim 1, I will use a novel pharmacological approach to perform circuit-level and behavioral analyses of FS interneuron regulation of direct and indirect pathway activity. Because interneurons are powerful regulators of circuit function and are intimately involved in the pathology of several basal ganglia disorders, this pharmacological dissection of their role will provide new insights into Parkinson's disease and other disorders and may lead to new pharmaceutical treatments. In Aim 2-3, I will use optogenetics combined with slice and in vivo electrophysiology to challenge long-standing hypotheses about the organization of FS microcircuits. Long- standing theories about inputs to FS interneurons from the cortex and thalamus have shaped thinking about the organization of striatal microcircuits, but these dogmatic theories are based largely on experiments in other systems and have not been directly tested in the striatum. Using optogenetics in Aim 2, I will directly measure feedforward inhibition recruited by cortical and thalamic inputs to the striatum to directly challenge old ideas about the role of feedforward inhibition in striatal function and disease. In Aim 3, I will turn to FS inputs from the globus pallidus (GPe); although inputs from the GPe were identified anatomically over ten years ago, a detailed functional characterization of this projection has been sorely lacking. The identification of novel neural circuits that connect the GPe and striatum could challenge long-standing assumptions about information processing in the basal ganglia. Together, all of these experiments will advance our understanding of the neural circuitry that underlies motor control and potentially identify new targets for disease therapy.